Using a non-heparinized, unrestrained rat model of trauma-hemorrhagic shock and acute crystalloid resuscitation (Rs), our studies have shown that there is release of TNF and IL-6, depression of the function of several organs (heart, liver, kidney, gut and blood vessels) and late mortality. The limitations of the model, however, are that monitoring of cardiovascular and hemodynamic responses as well as fluid Rs, can be performed only acutely. Since trauma patients are continuously monitored and fluid management in hospitals and intensive-care units (ICU) is provided on an as needed basis, we hypothesize that the full extent of cell and organ dysfunction in experimental models can be more accurately assessed by following the initial trauma-hemorrhagic insult, with a period of fluid optimization measured with close monitoring similar to an ICU setting. We also hypothesize that optimization of intravascular fluid volume in a chronic model of fluid optimization after hemorrhage may delay the progressive deterioration of cell and organ function but that fluids alone will not be sufficient to prevent the problems. Consequently, pharmacologic agents as adjuncts to fluid Rs will be needed. Studies are proposed to determine: l) the feasibility of establishing an extended model of monitoring blood pressure (BP), central venous pressure (CVP), circulating blood volume (CBV), urine output, cardiac output (CO), hepatocellular function and blood flow in a non-heparinized normal rat model with the aid of a computer-based data acquisition system for measurements and infusion of maintenance fluids; 2) the feasibility of chronically monitoring the above parameters following trauma-hemorrhage and acute Rs; 3) whether long-term optimization of intravascular fluid volume after trauma-hemorrhage/Rs with fluid administration on an as needed basis delays the deterioration of cardiovascular, hemodynamic, cell and organ function: 4) the mechanisms of cell and organ dysfunction after hemorrhage-Rs in a model involving acute fluid Rs vs the model which involves chronic Rs; 5) whether chemically modified heparin (without significant anticoagulant activity), ATP-MgCl2, diltiazem or pentoxifylline (which downregulate inflammatory cytokines) as an adjunct to Rs restores and maintains hemodynamic stability, cell and organ function and decreases the susceptibility to sepsis after injury and hemorrhage. The hemodynamic parameters and organ functions to be measured include mean BP, CVP, CBV, CO, hepatocellular function, renal, gut (absorptive capacity), and organ blood flow. Moreover, endothelium, enterocyte and hepatocyte function, hepatic alpha- and beta-adrenergic receptors, tissue adenine nucleotides, tissue and cell cAMP and cGMP levels, electrolytes and H2O contents, along with the release of selected mediators (TNF, IL-6, catecholamines) will be measured. We plan to determine if hemodynamic and cardiovascular stability is linked to CO, BP, CVP, urine output or CBV. The proposed studies involving chronic monitoring of various hemodynamic and cardiovascular parameters with fluid optimization following trauma-hemorrhage should provide useful information for the treatment and care of patients with major blood loss and for decreasing the susceptibility to subsequent sepsis.